This proposal focuses on the development of new methodology for the synthesis of several important classes of carbocyclic and heterocyclic organic compounds. New general strategies for the synthesis of ketenes will be investigated, and this chemistry will be applied to the synthesis of four-membered carbocycles and nitrogen heterocycles. Improved methodology for the preparation of cyclobutenone derivatives will be investigated. The scope and stereochemical course of a general [4+4] annulation approach to eight-membered carbocyclic compounds will be investigated. This reaction involves the thermal combination of 1,3-dienes and cyclobutenones to afford 2,6-cyclooctadienone derivatives. The application of this methodology to the synthesis of bicyclo[6.3.0]- and bicyclo[5.3.1] undecane derivatives, and also azabicyclo[4.2.1] nonanes will be examined. These systems are incorporated in the structures of several natural products including sesterterpenes of the ophiobolin family, the antibiotic pleuromutilin, the antitumor diterpene taxol, and the neurotoxic alkaloid anatoxin a.